HAO1 negatively regulates liver macrophage activation via the NF-κB pathway in alcohol-associated liver disease.

Inflammation is a key factor contributing to the progression of alcohol-associated liver disease (ALD). Accumulating data have shown that ethyl alcohol (EtOH) induced liver macrophages activation along with an inflammatory response that contributes to the development of ALD. The liver-specific peroxisomal enzyme hydroxyacid oxidase 1 (HAO1) has been found to be associated with chronic liver disease. But the role of HAO1 remains unknown in ALD. In our study, HAO1 was found to be decreased in ALD patients and EtOH-fed mice. Interestingly, HAO1 expression was reduced in primary hepatocytes, whereas HAO1 was elevated in peripheral blood monocytes from ALD patients and EtOH-fed mice liver macrophages as well as LPS-treated RAW264.7 cells. Moreover, HAO1 knockdown exacerbated the inflammatory response, while HAO1 overexpression inhibited inflammation in LPS-stimulated RAW264.7 cells. Additionally, overexpression or silencing of HAO1 in vitro significantly affected NF-κB signaling pathway. Collectively, the results revealed a key role of HAO1-mediated macrophage activation and may provide a potential target for treating ALD.